Heterocyclic compounds, their preparation and use

ABSTRACT

PCT No. PCT/DR96/00331 Sec. 371 Date Jan. 21, 1998 Sec. 102(e) Date Jan. 21, 1998 PCT Filed Jul. 31, 1996 PCT Pub. No. WO97/05137 PCT Pub. Date Feb. 13, 1997The present invention relates to a method of treating a disease in the central nervous system via the metabotropic glutamate receptor system, the use of the known as well as novel pyridino(2,3-b) indoles (formula Ib) for the preparation of a medicament for treating said diseases, novel therapeutic active pyridino(2,3-b) indoles, a method for preparing the same and pharmaceutical compositions comprising these compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a 35 U.S.C. 371 national application ofPCT/DK96/00331 filed Jul. 31, 1996 published as WO 97/05137 on Feb. 13,1997 and claims priority under 35 U.S.C. 119 of Danish application0868/95 filed Jul. 31, 1995, the contents of which are fullyincorporated herein by reference.

The present invention relates to a method of treating a disease in thecentral nervous system via the metabotropic glutamate receptor system,the use of known as well as new pyridino 2,3-b!indoles for thepreparation of a medicament for treating said diseases, noveltherapeutic active pyridino 2,3-b!indoles, a method for preparing thesame and pharmaceutical compositions comprising these compounds.

Recent molecular biological studies have clearly established theexistence of two major types of glutamate receptors in the centralnervous system namely the ionotropic and the metabotropic glutamatereceptors. The latter is characterised by being G-protein-linked tochanges in second messenger formation and modulation of ion channelfunction, (Meldrum, B. (1991) Epilepsy Res. 10, 55-61, Chapman, A.(1991) in Excitatory Amino Acids p. 265-286, Blackwell scientific publ.ltd., Oxford).

At present 8 different subtypes of the metabotropic glutamate receptorsare described (MGluR₁ to MGluR₈) and in addition some spliced variantsof the subtypes are reported.

The Metabotropic glutamate receptor subtypes MGluR₁ and MGluR₅ arecoupled to phosphoinositide hydrolysis (Johnson, G. and Bigge, C. F.(1991) Annu. Rep. Med. Chem. 26, 11-22, Hansen, J. J. and KrogsgaardLarsen, P. Med. Res. Rev. 10,55-94, Thomsen, C. and Suzdak, P. (1993)Eur. J. Pharmacol. 245 ,299), while the others are coupled to cyclic AMPformation (Schoepp, D. D., Johnson, B. G. and Monn, J. A. (1992) J.Neurochem. 58, 1184-1186, Cartmell et al. (1992) J. Neurochem. 58,1964-1966, Manzoni, O. et al. (1992) Eur. J. Pharmacol. 225, 357-358).

Compounds such as L-glutamate, quisqualate and ibotenate are known toact as non-selective agonists on the metabotropic glutamate receptors,while selective ionotropic glutamate receptor agonists such as NMDA,AMPA and kainate have little effect on these receptors.

Recently a few compounds without activity at the ionotropic glutamatereceptors but with activity at the metabotropic receptors have beenidentified.

These comprise trans-ACPD (trans1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid), the partial agonistL-AP3 (L-2-amino-3-phosphonopropionic acid) (Palmer, E., Monaghan, D. T.and Cotman, C. W. (1989) Eur. J. Pharmacol. 166, 585-587, Desai, M. A.and Conn, P. J. (1990) Neurosci. Lett. 109, 157-162, Schoepp, D. D. etal. (1991), J. Neurochem. 56, 1789-1796, Schoepp D. D. and Johnson B. G.(1989), J. Neurochem. 53,1865-1613), L-AP4(L-2-amino4-phosphonobutyrate) which is an agonist at the MGluR₄receptor (Thomsen C. et al. (1992), Eur. J. Pharmacol. 227, 361-362) andsome of the isomers of CCG (2-(carboxycyclopropyl)glycines) especiallyL-CCG-I and L-CCG-II (Hayashi, Y. et al. (1992), Br. J. Pharmacol. 107,539-543).

Very few selective antagonists at the metabotropic glutamate receptorshave been reported, however some phenylglycine derivatives S-4CPG(S-4-carboxyphenyl glycine), S-4C3HPG (S-4-carboxy-3-hydroxyphenylglycine) and S-MCPG (S-alpha methyl4-carboxyphenyl glycine) have beenreported to antagonise trans ACPD stimulated phosphoinositide hydrolysisand thus possibly acting as antagonists at the metabotropic glutamatereceptors at the subtypes MGluR₁ and MGluR₅ (Thomsen, C. and Suzdak, P,(1993) Eur. J. Pharmacol. 245, 299).

Literature evidence suggests that compounds selective for themetabotropic glutamate receptors either as agonists or antagonists areuseful in the treatment of different neurological diseases.

The use of compounds active at the metabotropic glutamate receptors forthe treatment of epilepsy is corroborated by investigations of theinfluence of trans-ACPD in the formation of convulsions (Sacaan andSchoepp, (1992), Neurosci. lett. 139, 77) and that phosphoinositidehydrolysis mediated via MGluR is increased after kindling experiments inrats (Akiyama et al. (1992),Brain Res. 569, 71).

Trans-ACPD has been shown to increase release of dopamine in the ratbrain which indicates that compounds acting on the metabotropicglutamate receptors might be usable for the treatment of Parkinson'sdisease and Huntington's Chorea (Sacaan et al. (1992), J. Neurochem. 59,245).

The use of compounds active at the metabotropic glutamate receptors fortreatment of neurological diseases such as senile dementia has beenindicated by the findings of Zheng and Gallagher ((1992), Neuron 9, 163)and Bashir et al. ((1993), Nature 363, 347) who demonstrated thatactivation of metabotropic glutamate receptors are necessary for theinduction of long term potentiation (LTP) in nerve cells (septalnucleus,hippocampus) and the finding that long term depression isinduced after activation of metabotropic glutamate receptors incerebellar granule cells (Linden et al. (1991), Neuron 7,81).

Investigations also show that in the treatment of deficiencies of mentaland motoric performance seen after conditions of brain ischemia themetabotropic glutamate receptor active compounds may prove usable.

Trans-ACPD has been shown to be a neuroprotective agent in an MCAO modelin mice (Chiamulera et al. (1992), Eur. J. Pharmacol. 215, 353), and ithas been shown to inhibit NMDA induced neurotoxicity in nerve cellcultures (Koh et al., (1991), Proc. Natl. Acad. Sci. USA 88, 9431).

Also in the treatment of pain the metabotropic glutamate receptor activecompounds seem of interest, proved by the fact that antagonists at themetabotropic glutamate receptors antagonises sensory synaptic responseto noxious stimuli of thalamic neurons (Eaton, S. A. et al. (1993), Eur.J. Neurosci. 5, 186).

The above findings support that compounds acting on the metabotropicglutamate receptors are useful for the treatment of epilepsy,neurological diseases such as senile dementia, Parkinson's disease,Huntington's Chorea, pain and deficiencies of mental and motoricperformance seen after conditions of brain ischemia.

We have now discovered that a series of pyridino 2,3-b!indoles, some ofwhich compounds are known from GB 1 268 772 (Glaxo Laboratories Ltd.) topossess antiviral activity, are potent antagonists at the metabotropicglutamate receptors.

Thus the present invention is concerned with a method of treating adisease in the central nervous system via the metabotropic glutamatereceptor system comprising administering to a subject in need thereof aneffective amount of a compound of formula Ib ##STR2## wherein R^(1b) isH; C₁₋₆ -alkyl optionally substituted with halogen; C₂₋₆ -alkenyl; C₂₋₆-alkynyl; C₃₋₆ -cycloalkyl; C₁₋₆ -alkyl substituted with C₃₋₆-cycloalkyl; carboxy; --COR^(9b) ;---COOR^(9b) ; C₁₋₆ -alkyl substitutedwith dimethylamino;

--R^(9b) --O--R^(10b) ; --R^(9b) --O--R^(10b) --O--R^(11b) ;phenylsulfonyl; benzoyl; benzyl or phenyl each of which aromatic groupis optionally substituted with C₁₋₆ -alkyl, C₁₋₆ -alkoxy, halogen,carboxy or nitro; wherein R^(9b), R^(10b), R^(11b) and are independentlyC₁₋₆ -alkyl;

R^(2b) is amino optionally substituted with one or two C₁₋₆ -alkyl whichalkyl group(s) is/are optionally substituted with hydroxy, morpholino,amino unsubstituted or mono or disubstituted with C₁₋₆ -alkyl, phenyl,phenylsulfonyl or benzyl; piperidino; morpholino; or piperazinooptionally N-substituted with C₁₋₆ -alkyl;

R^(3b) is H; carboxy; cyano; nitro; C₁₋₆ -alkyl optionally substitutedwith hydroxy; --R^(9b) --O--R^(10b) ; --COOR^(9b) ; wherein R^(9b) andR^(10b) are as defined above; morpholinocarbonyl;thiomorpholinocarbonyl; piperazinylcarbonyl optionally substituted withC₁₋₆ -alkyl; tetrazolyl; oxadiazolyl or thiadiazolyl optionallysubstituted with C₁₋₆ -alkyl or C₃₋₆ -cycloalkyl; morpholinomethyl;amino unsubstituted or mono or disubstituted with C₁₋₆ -alkyl;methylamino unsubstituted or N-mono or disubstituted with C₁₋₆ -alkyl;sulfamoyl unsubstituted or mono or disubstituted with C₁₋₆ -alkyl; orcarbamoyl unsubstituted or mono or disubstituted with C₁₋₆ -alkyl whichalkyl group(s) is/are optionally substituted with dimethylaminomethyl,halogen, phenyl or benzyl;

R^(4b) is H; or C₁₋₆ -alkyl;

R^(5b), R^(6b), R^(7b), and R^(8b) are independently H; nitro; amino;halogen; trifluoromethyl; trifluoroacetyl; sulfo; carboxy; carbamoyl;sulfamoyl; --COR^(9b) ; --COOR^(9b) ; wherein R^(9b) is as definedabove; C₁₋₆ -alkoxy; or C₁₋₆ -alkyl optionally substituted with halogen;

or a salt thereof with a pharmaceutically acceptable acid or base.

These salts include pharmaceutically acceptable acid addition salts,pharmaceutically acceptable metal salts or optionally alkylated ammoniumsalts, such as hydrochloric, hydrobromic, hydroiodic, phosphoric,sulfuric, trifluoroacetic, trichloroacetic, oxalic, maleic, pyruvic,malonic, succinic, citric, tartaric, fumaric, mandelic, benzoic,cinnamic, methanesulfonic, ethane sulfonic, picric and the like, andinclude acids related to the pharmaceutically acceptable salts listed inJournal of Pharmaceutical Science, 66, 2 (1977) and incorporated hereinby reference, or lithium, sodium, potassium, magnesium and the like.

The term "C₁₋₆ -alkyl" as used herein, alone or in combination, refersto a straight or branched, saturated hydrocarbon chain having 1 to 6carbon atoms such as e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl,sec.butyl, isobutyl, tert.butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl,n-hexyl, 4-methylpentyl, neopentyl, n-hexyl and 2,2-dimethylpropyl.

The term "C-₁₋₆ -alkoxy" as used herein, alone or in combination, refersto a monovalent substituent comprising a lower alkyl group linkedthrough an ether oxygen having its free valence bond from the etheroxygen and having 1 to 6 carbon atoms e.g. methoxy, ethoxy, propoxy,butoxy, pentoxy.

The term "C₂₋₆ -alkenyl" as used herein refers to an unsaturatedhydrocarbon chain having 2-6 carbon atoms and one double bond such ase.g. vinyl, 1-propenyl, allyl, isopropenyl, n-butenyl, n-pentenyl andn-hexenyl.

The term "C₃₋₆ -cycloalkyl" as used herein refers to a radical of asaturated cyclic hydrocarbon with the indicated number of carbons suchas cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

The term "C₂₋₆ -alkynyl" as used herein refers to unsaturatedhydrocarbons which contain triple bonds, such as e.g. --C.tbd.CH,--C.tbd.CCH₃, --CH₂ C.tbd.CH, --CH₂ CH₂ C.tbd.CH, --CH(CH₃)C.tbd.H, andthe like.

The term "halogen" means fluorine, chlorine, bromine and iodine.

It is to be understood that the invention extends to the use of each ofthe stereoisomeric forms of the compounds of formula Ib as well as theracemates.

In the method of the present invention, R^(1b) is preferably benzyloptionally substituted with C₁₋₆ -alkyl, C₁₋₆,-alkoxy, halogen, carboxyor nitro, more preferably benzyl optionally substituted with halogen;R^(2b) is preferably piperidino; morpholino; or piperazino optionallyN-substituted with C₁₋₆ -alkyl; more preferably morpholino; and R^(3b)is preferably carboxy.

The present invention furthermore relates to the use of compounds offormula Ib for the preparation of a medicament for treatment of adisease in the central nervous system via the metabotropic glutamatereceptor system.

In addition, the present invention is concerned with novel compounds offormula Ib ##STR3## wherein R^(1b) is benzyl optionally substituted withC₁₋₆ -alkyl, C₁₋₆ -alkoxy, halogen, carboxy or nitro, preferably benzyloptionally substituted with halogen;

R^(2b) is piperidino; morpholino; or piperazino optionally N-substitutedwith C₁₋₆ -alkyl; preferably morpholino;

R^(3b) is H; carboxy; cyano; nitro; C₁₋₆ -alkyl optionally substitutedwith hydroxy; --R^(9b) --O--R^(10b) ; --COOR^(9b) ; wherein R^(9b) andR^(10b) are as defined above; morpholinocarbonyl;thiomorpholinocarbonyl; piperazinylcarbonyl optionally substituted withC₁₋₆ -alkyl; tetrazolyl; oxadiazolyl or thiadiazolyl optionallysubstituted with C₁₋₆ -alkyl or C₃₋₆ -cycloalkyl; morpholinomethyl;amino unsubstituted or mono or disubstituted with C₁₋₆ -alkyl;methylamino unsubstituted or N-mono or disubstituted with C₁₋₆ -alkyl;sulfamoyl unsubstituted or mono or disubstituted with C₁₋₆ -alkyl; orcarbamoyl unsubstituted or mono or disubstituted with C₁₋₆ -alkyl whichalkyl group(s) is/are optionally substituted with dimethylaminomethyl,halogen, phenyl or benzyl; preferably carboxy.

R^(4b) is H; or C₁₋₆ -alkyl;

R^(5b), R^(6b), R^(7b), and R^(8b) are independently H; nitro; amino;halogen; trifluoromethyl; trifluoroacetyl; sulfo; carboxy; carbamoyl;sulfamoyl; --COR^(9b) ; --COOR^(9b) ; wherein R^(9b) is as definedabove; C₁₋₆ -alkoxy; or C₁₋₆ -alkyl optionally substituted with halogen;or a salt thereof with a pharmaceutically acceptable acid or base.

Specific examples of compounds of the invention include the following:

Ethyl 9-benzyl-2-piperidinopyridino 2,3-b!indole-3-carboxylate,

Ethyl 9-benzyl-2-morpholinopyridino 2,3-b!indole-3-carboxylate,

9-Benzyl-2-morpholinopyridino 2,3-b!indole-3-carboxylic acid,

9-Benzyl-2-morpholinopyridino 2,3-b!indole,

9-Benzyl-2-piperidinopyridino 2,3-b!indole.

The compounds of formula Ib may e.g. be prepared in accordance with theteaching of GB 1 268 772. However, the invention also relates to anadvantageous method of preparing the above mentioned compounds. Thismethod comprises

a) reacting a compound of formula IIb, ##STR4## prepared by well knownmethods, wherein R^(1b), R^(5b), R^(6b), R⁷ b and R^(8b) have themeanings defined above, with a N,N-dimethyl amide, preferablydimethylformamide or dimethylacetamide, and POX₃, wherein X is chlorineor bromine, using Vilsmeyer-Hack conditions, to form a compound offormula IIIb, ##STR5## wherein X is chlorine or bromine, and R^(1b),R^(4b), R^(5b), R^(6b), R^(7b), and R^(8b) have the meanings definedabove; and subsequently

b) reacting a compound of formula IIIb, wherein X is chlorine orbromine, and R^(1b), R^(4b), R^(5b), R^(6b), R^(7b), and R^(8b) have themeanings defined above, with a compound N.tbd.C--CH₂ -Z^(b) whereinZ^(b) is cyano, nitro, COOR^(9b) wherein R^(9b) have the meaningsdefined above, sulfamoyl unsubstituted or mono or disubstituted withC₁₋₆ -alkyl, or carbamoyl unsubstituted or mono or disubstituted withC₁₋₆ -alkyl; together with an amine as defined for R^(2b), preferablymorpholine or piperidine, either in the presence or absence of an addedstrong base, such as sodium hydride, to form a compound of formula IVb,wherein Z^(b), R^(1b), R^(2b), R^(4b), R^(5b), R^(6b), R^(7b), andR^(8b) have the meanings defined above, or ##STR6## c) reacting acompound of formula IVb, wherein Z^(b), R^(1b), R^(2b), R^(4b), R^(5b),R^(6b), R^(7b), and R^(8b) have the meanings defined above, by means ofwell known chemical reactions transforming the Z^(b) group to hydrogenor to other functional groups such as acids, esters, amides, amines, orreaction products thereof as described for R^(3b), to form a compound offormula Ib, wherein R^(1b), R^(2b), R^(3b), R^(4b), R^(5b), R^(6b),R^(7b), and R^(8b) have the meanings defined above, or

d) reacting a compound of formula formula Ib, wherein R^(1b), R^(2b),R^(3b), and R^(4b) have the meanings defined above, and at least one ofR^(5b), R^(6b), R^(7b), or R^(8b) is H with well known reactivesubstrates leading to aromatic substitution using the reactionconditions known in the art, to form a compound of formula Ib, whereinR^(5b), R^(6b), R^(7b), or R^(8b) have the meanings defined aboveprovided that at least one of R^(5b), R^(6b), R^(7b), or R^(8b) is notH, or

e) a compound of formula Ib or formula IIb or formula IVb with differentR^(5b), R^(6b), R^(7b), or R^(8b) could be prepared by usingconventional organic chemistry on functional groups already introducedas R^(5b), R^(6b), R^(7b), or R^(8b) groups.

The pharmacological properties of the compounds of the invention can beillustrated by determining their effects in different conventionalradioligand binding assays or in functional in vitro assays.

The compounds of the invention were studied in an in vitro assay formeasuring inhibition of Pi-hydrolysis in BHK 570 cells expressing mGluR₁α receptors.

Principle

The metabotropic glutamate receptor (mGluR) is selectively activated bytrans-aminocyclopentane dicarboxylic acid and is coupled to thehydrolysis of inositol phosphates via a GTP-binding protein. At themolecular level, cDNAs encoding six subtypes of the mGluR family havebeen isolated. The first subtype isolated (Houamed et al., 1991, Science252, 1318), termed the mGluR1α, has been shown to be coupled toPl-hydrolysis when expressed in baby hamster kidney cells (BHK) (Thomsenet al., Brain Res. (in press)). In these cells no stimulation by 1 mMquisqualate or glutamate was observed with control BHK cells whereas a6-8 fold increase over basal Pl-hydrolysis was seen with BHK cellsexpressing mGluR1α.

Cell Culture

BHK570 cells expressing mGluR1α are cultured in DMEM (4.5 g/l glucose, 2mM glutamin); 5% foetal calf serum; 0.10 mg/ml neomycin; 0.5 mg/ml G418;1 μM methotrexate; 50 μg/ml gentamycin. Cells are subcultured every 5days using 0.05% trypsin/EDTA in PBS.

Inositol Phosphate Formation

The protocol for Pl-hydrolysis was measured using a modification of amethod previously described (Berridge et al., 1982, Biochem. J.206,587). Cells were plated in 16 mm wells (24 well multidish, Costar)with 1 confluent 100 mm dish per multidish. Replace the medium 24 hbefore the experiment with 500 μl fresh growth medium containing 4μCi/ml myo- 2-³ H!inositol (specific activity 18 Ci/mmol, Amersham). Thecells were washed twice with

Krebs-Henseleit buffer (Sigma cat. #3753: glucose 2.0 g/l, MgSO₄ 0.141g/l, KHPO₄ 0.16 g/l, KCl 0.35 g/l, NaCl 6.90 g/l and NaHCO₃ 2.1 g/l)supplemented with 10 mM LiCl and 2.5 mM CaCl₂. The buffer wasequilibrated with 5% CO₂, 95% air to pH 7.5 at 37° C. Following 5 min ofpreincubation in the above buffer, buffer or test compounds were addedand cells were incubated for 30 min at 37° C. In antagonist studies, addtest compounds 5 min prior to agonist stimulation. Pl-formation wasstopped by placing the cells on ice and quickly aspirating the media.The wells were washed once with ice-cold Krebs-Henseleit buffer andsubsequently 1 ml ice-cold 10% perchloric acid was added to each well.Place the cells on ice for 20 min. In Nunc minisorp test tubes (75×12mm, cat. #443990): add 250 μl of 10 mM EDTA, pH 7.0 +5% UniversalIndicator (Merck). Transfer the PCA extract to each tube containing thepH-indicator. Neutralize the samples with 1.5 M KOH+60 mM HEPES to pH7.5 (˜1100-1200 μl). Centrifugate (6.000 rpm, 5 min, 0° C.). They can bestored frozen at this point. Fractions of inositolphosphates wereseparated using ion-exchange columns (Amersham, RPN 1908) according tothe method provided by Amersham.

Separation of inositol phoshates on ion-exchange columns

Prepare columns with 5 ml 1 M KHCO₃ and wash with 15 ml dist. water.Adjust vacuum so that the flow-rate does not exceed 5 ml/min. Add 4 mldist. water and subsequently 1 ml ³ H!InsP sample. Wash with 5 ml dist.water. IP1 to IP4 fractions may be collected with 5 ml 0.05; 0.10; 0.17and 0.25 M KHCO₃, respectively. Usually IP1 and IP2 fractions arecollected simultaneously. Scintillation liquid: use 12-15 ml Ultima Gold(Packard).

Testprocedure

Testcompounds are dissolved in DMSO, DMSO and Pluronic F-127 or ethanoland diluted in assay buffer. Glutamate (10 μM and 1000 μM) and bufferalone are included as a control.

Results

The stimulation by 10 μM shall represent a submaximal stimulation. Theresponse by 10 μM glutamate should exceed 3-fold the basal level andshould be below maximal stimulation (glutamate at 1 mM). The results arecalculated relative to the stimulation by 10 μM glutamate and a doseresponse curve is generated.

An example of a test result obtained by testing a compound of thepresent invention in the above mentioned assay appear from the followingTable 1.

                  TABLE 1                                                         ______________________________________                                        Compound No.   IC.sub.50 (μM)                                              ______________________________________                                        3              10                                                             ______________________________________                                    

The compounds according to the invention are effective over a widedosage range. For example, in the treatment of adult humans, dosagesfrom about 0.05 to about 100 mg, preferably from about 0.1 to about 100mg, per day may be used. A most preferable dosage is about 10 mg toabout 70 mg per day. In choosing a regimen for patients suffering from adisease in the central nervous system related to the metabotropicglutamate receptor system it may frequently be necessary to begin with adosage of from about 30 to about 70 mg per day and when the condition isunder control to reduce the dosage as low as from about 1 to about 10 mgper day. The exact dosage will depend upon the mode of administration,form in which administered, the subject to be treated and the bodyweight of the subject to be treated, and the preference and experienceof the physician or veterinarian in charge.

The route of administration may be any route, which effectivelytransports the active compound to the appropriate or desired site ofaction, such as oral or parenteral e.g. rectal, transdermal,subcutaneous, intravenous, intramuscular or intranasal, the oral routebeing preferred.

Typical compositions include a compound of formula Ib or apharmaceutically acceptable acid addition salt thereof, associated witha pharmaceutically acceptable carrier. In making the compositions,conventional techniques for the preparation of pharmaceuticalcompositions may be used. For example, the active compound will usuallybe mixed with a carrier, or diluted by a carrier, or enclosed within acarrier which may be in the form of a ampoule, capsule, sachet, paper,or other container. When the carrier serves as a diluent, it may besolid, semi-solid, or liquid material which acts as a vehicle,excipient, or medium for the active compound. The active compound can beadsorbed on a granular solid container for example in a sachet. Someexamples of suitable carriers are water, salt solutions, alcohols,polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine,lactose, amylose, magnesium stearate, talc, silicic acid, fatty acidmonoglycerides and diglycerides, pentaerythritol fatty acid esters,hydroxymethylcellulose and polyvinylpyrrolidone.

The pharmaceutical preparations can be sterilized and mixed, if desired,with auxiliary agents, emulsifiers, salt for influencing osmoticpressure, buffers andlor coloring substances and the like, which do notdeleteriously react with the active compounds.

For parenteral application, particularly suitable are injectablesolutions or suspensions, preferably aqueous solutions with the activecompound dissolved in polyhydroxylated castor oil.

Tablets, dragees, or capsules having talc and/or a carbohydrate carrieror binder or the like are particularly suitable for oral application.Preferable carriers for tablets, dragees, or capsules include lactose,corn starch, and/or potato starch. A syrup or elixir can be used incases where a sweetened vehicle can be employed.

Generally, the compounds are dispensed in unit form comprising fromabout 1 to about 100 mg in a pharmaceutically acceptable carrier perunit dosage.

A typical tablet, appropriate for use in this method, may be prepared byconventional tabletting techniques and contains:

    ______________________________________                                        Active compound    5.0    mg                                                  Lactosum           67.8   mg Ph.Eur.                                          Avicel ®       31.4   mg                                                  Amberlite ®    1.0    mg                                                  Magnesii stearas   0.25   mg Ph.Eur.                                          ______________________________________                                    

The invention will now be described in further detail with reference tothe following examples.

EXAMPLE 1b Ethyl 9-benzyl-2-piperidinopyridino2,3-b!indole-3-carboxylate (1b)

To a slurry of 1.35 g of 1-benzyl-2-chloroindole-3-carbaldehyde in 30 mlabs. EtOH was added 1 ml of ethyl cyanoacetate and 3.5 ml of piperidine,and the mixture was stirred at room temperature for 2.5 days. 30 ml ofice/water was added, and the precipitate was isolated by filtration anddried to give (1b). Yield 1.6 g of (1b), m.p. 155-156° C.

EXAMPLE 2b Ethyl 9-benzyl-2-morpholinopyridino2,3-b!indole-3-carboxylate (2b)

To a slurry of 1.35 g of 1-benzyl-2-chloroindole-3-carbaldehyde in 30 mlabs. EtOH was added 1.5 ml of ethyl cyanoacetate and 3.5 ml ofmorpholine, and the mixture was stirred at room temperature for 2 days.The mixture was then heated to reflux for 5 hours, cooled to roomtemperature and filtered to give (2b). Yield 1.6 g of (2b), m.p.151-152° C.

EXAMPLE 3b 9-Benzyl-2-morpholinopyridino 2,3-b!indole-3-carboxylic acid(3b)

1.3 g of (2b) was covered with a solution of 200 mg of KOH in 2 ml ofwater, and stirred at room temperature for 1 hour and at 60° C. for 2hours. After cooling the solvent was evaporated and the productprecipitated with water and acetic acid to give 1.1 g of a mixture of 2compounds. These two products were separated by column chromatography,on Silica 60 using methanol and methylenedichloride 1+9 as the eluent,to give (3b). Yield 480 mg of (3b). An analytical sample wasrecrystallized from EtOH, m.p. 282-287° C.

We claim:
 1. A method of treating a disease in the central nervoussystem via the metabotropic glutamate receptor system comprisingadministering to a subject in need thereof an effective amount of acompound of formula Ib ##STR7## wherein R^(1b) is H; C₁₋₆ -alkyloptionally substituted with halogen; C₂₋₆ -alkenyl; C₂₋₆ -alkynyl; C₃₋₆-cycloalkyl; C₁₋₆ -alkyl substituted with C₃₋₆ -cycloalkyl; carboxy;--COR^(9b) ; --COOR^(9b) ; C₁₋₆ -alkyl substituted with dimethylamino;--R^(9b) --O--R^(10b) ; --R^(9b) --O--R^(10b) --O--R^(11b) ;phenylsulfonyl; benzoyl; benzyl or phenyl each of which aromatic groupis optionally substituted with C₁₋₆ -alkyl, C₁₋₆ -alkoxy, halogen,carboxy or nitro; wherein R^(9b), R^(10b) and R^(11b) are independentlyC₁₋₆ -alkyl;R^(2b) is amino optionally substituted with one or two C₁₋₆-alkyl which alkyl group(s) is/are optionally substituted with hydroxy,morpholino, amino unsubstituted or mono- or disubstituted with C₁₋₆-alkyl, phenyl, phenylsulfonyl or benzyl; piperidino; morpholino; orpiperazino optionally N-substituted with C₁₋₆ -alkyl; R^(3b) is H;carboxy; cyano; nitro; C₁₋₆ -alkyl optionally substituted with hydroxy;--R^(9b) --O--R^(10b) ; --COOR^(9b) ; wherein R^(9b) and R^(10b) areindependently C₁₋₆ -alkyl; morpholinocarbonyl; thiomorpholinocarbonyl;piperazinylcarbonyl optionally substituted with C₁₋₆ -alkyl; tetrazolyl;oxadiazolyl or thiadiazolyl optionally substituted with C₁₋₆ -alkyl orC₃₋₆ -cycloalkyl; morpholinomethyl; amino unsubstituted or mono- ordisubstituted with C₁₋₆ -alkyl; methylamino unsubstituted or N-mono- ordisubstituted with C₁₋₆ -alkyl; sulfamoyl unsubstituted or mono- ordisubstituted with C₁₋₆ -alkyl; or carbamoyl unsubstituted or mono- ordisubstituted with C₁₋₆ -alkyl which alkyl group(s) is/are optionallysubstituted with dimethylaminomethyl, halogen, phenyl or benzyl; R^(4b)is H; or C₁₋₆ -alkyl; R^(5b), R^(6b), R^(7b), and R^(8b) areindependently H; nitro; amino; halogen; trifluoromethyl;trifluoroacetyl; sulfo; carboxy; carbamoyl; sulfamoyl; --COR^(9b) ;--COOR^(9b) ; wherein R^(9b) is C₁₋₆ -alkyl; C₁₋₆ -alkoxy; or C₁₋₆-alkyl optionally substituted with halogen; or a salt thereof with apharmaceutically acceptable acid or base.
 2. A method according to claim1 wherein R^(1b) is benzyl optionally substituted with C₁₋₆ -alkyl, C₁₋₆-alkoxy, halogen, carboxy or nitro.
 3. A method according to claim 2wherein R^(1b) is benzyl optionally substituted with halogen.
 4. Amethod according to claim 1 wherein R^(2b) is piperidino; morpholino; orpiperazino optionally N-substituted with C₁₋₆ -alkyl.
 5. A methodaccording to claim 4 wherein R^(2b) is morpholino.
 6. A method accordingto claim 1 wherein R^(3b) is carboxy.
 7. A method according to claim 1wherein the compound of formula Ib is selected from the group consistingof:Ethyl 9-benzyl-2-piperidinopyridino 2,3-b!indole-3-carboxylate, Ethyl9-benzyl-2-morpholinopyridino 2,3-b!indole-3-carboxylate,9-Benzyl-2-morpholinopyridino 2,3-b!indole-3-carboxylic acid,9-Benzyl-2-morpholinopyridino 2,3-b!indole,9-Benzyl-2-piperidinopyridino 2,3-b!indole.
 8. A method according toclaim 1 wherein the disease is epilepsy, senile dementia, Parkinson'sdisease, Huntington's Chorea, pain or deficiencies of mental and motoricperformance seen after conditions of brain ischemia.
 9. A compound offormula Ib ##STR8## wherein R^(1b) is benzyl optionally substituted withC₁₋₆ -alkyl, C₁₋₆ -alkoxy, halogen, carboxy or nitro;R^(2b) ispiperidino; morpholino; or piperazino optionally N-substituted with C₁₋₆-alkyl; R^(3b) is; carboxy; cyano; nitro; C₁₋₆ -alkyl optionallysubstituted with hydroxy; --R^(9b) --O--R^(10b;) --COOR^(9b) ; whereinR^(9b) and R^(10b) are independently C₁₋₆ -alkyl; morpholinocarbonyl;thiomorpholinocarbonyl; piperazinylcarbonyl optionally substituted withC₁₋₆ -alkyl; tetrazolyl; oxadiazolyl or thiadiazolyl optionallysubstituted with C₁₋₆ -alkyl or C₃₋₆ -cycloalkyl; morpholinomethyl;amino unsubstituted or mono- or disubstituted with C₁₋₆ -alkyl;methylamino unsubstituted or N-mono- or disubstituted with C₁₋₆ -alkyl;sulfamoyl unsubstituted or mono- or disubstituted with C₁₋₆ -alkyl; orcarbamoyl unsubstituted or mono- or disubstituted with C₁₋₆ -alkyl whichalkyl group(s) is/are optionally substituted with dimethylaminomethyl,halogen, phenyl or benzyl; R^(4b) is H; or C₁₋₆ -alkyl; R^(5b), R^(6b),R^(7b), and R^(8b) are independently H; nitro; amino; halogen;trifluoromethyl; trifluoroacetyl; sulfo; carboxy; carbamoyl; sulfamoyl;--COR^(9b) ; --COOR^(9b) ; wherein R^(9b) is C₁₋₆ -alkyl; C₁₋₆ -alkoxy;or C₁₋₆ -alkyl optionally substituted with halogen; or a salt thereofwith a pharmaceutically acceptable acid or base.
 10. A compoundaccording to claim 9 wherein R^(1b) is benzyl optionally substitutedwith halogen.
 11. A compound according to claim 9 wherein R^(2b) ismorpholino.
 12. A compound according to claim 9 wherein R^(3b) iscarboxy.
 13. A compound according to claim 10 wherein R^(2b) ismorpholino.
 14. A compound according to claim 10 wherein R^(3b) iscarboxy.
 15. A compound according to claim 11 wherein R^(3b) is carboxy.16. A compound according to claim 9 wherein R^(1b) is benzyl, R^(2b) ismorpholino, and R^(3b) is carboxy.
 17. A compound according to claim 13wherein R^(5b), R^(6b), R^(7b) and R^(8b) are hydrogen.
 18. A compoundaccording to claim 14 wherein R^(5b), R^(6b), R^(7b) and R^(8b) arehydrogen.
 19. A compound according to claim 15 wherein R^(5b), R^(6b),R^(7b) and R^(8b) are hydrogen.
 20. A compound according to claim 16wherein R^(5b), R^(6b), R^(7b) and R^(8b) are hydrogen.
 21. A compoundaccording to claim 9 wherein R^(1b) is ethylbenzyl, R^(2b) ispiperidino, and R^(3b) is carboxylate, and R^(4b), R^(5b), R^(6b),R^(7b), R^(8b) are hydrogen.
 22. A compound according to claim 9 whereinR^(1b) is ethylbenzyl, R^(2b) is morpholino, and R^(3b) is carboxylateand R^(4b), R^(5b), R^(6b), R^(7b) and R^(8b) are hydrogen.
 23. Acompound according to claim 9 wherein R^(1b) is benzyl, R^(2b) ismorpholino, and R^(3b) is carboxylate and R^(4b), R^(5b), R^(6b), R^(7b)and R^(8b) are hydrogen.
 24. A compound according to claim 9 whereinR^(1b) is benzyl, R^(2b) is morpholino, and R^(4b), R^(5b), R^(6b),R^(7b) and R^(8b) are hydrogen.
 25. A compound according to claim 9wherein R^(1b) is benzyl, R^(2b) is piperidino, and R^(4b), R^(5b),R^(6b), R^(7b) and R^(8b) are hydrogen.
 26. A pharmaceutical compositioncomprising a compound according to claim 9 together with apharmaceutically acceptable carrier or diluent.
 27. The pharmaceuticalcomposition according to claim 26 in the form of an oral dosage unit orparenteral dosage unit.
 28. The pharmaceutical composition according toclaim 27, wherein said dosage unit comprises from about 1 mg to about100 mg of the compound.